Process for converting optically active aminodiols into racemic aminodiols by oxidation followed by racemization



United States PROCESS FOR CONVERTING OPTICALLY ACTIVE AMINODIOLS INTO RACEMIC AMINODIOLS BY OXIDATION FOLLOWED BY RACEMIZATION :Carlo Giuseppe Alberti, Luigi Bernardi, Giovanni and Alberto Vercellone, all of Milan, Italy, assignors to Socreta Farmaceutici I Milan, Italy, a corporation of Italy No Drawing. Filed Aug. 14, 1956, Ser. No. 603,869 Claims priority, application Italy May 20, 1953 11 Claims. 01. 260-562 Our invention relates to a process for converting optically active ammodiols into racemic amino-diols. It is a continuation-impart of our copending application Serial No. 432,034, filed May 24, 1954, now abandoned.

-It is known that chloramphenicol is a derivative of phenyl amino propanediol, namely D-threo-l-p-nitrophenyl-2-dichloroacetamido-1,3-propanediol, an optically active compound. Since synthesis methods always yield racemic compounds, in chloramphenicol synthesis it is necessary to carry out a resolution into the optical isoof the final product chloramphenicol. If the intermediate chosen is a threo-phenylaminopropanediol, of the two optical isomers obtained, D- and L-, it is the D-isomer that is employed for the further steps of the'synthesis, the L-isomer being discarded. If the intermediate reatent "ice 2,945,883 Patented July 19, 1960 2. .tives of the phenyl aminopropanediols to obtain the a-acylamino-[i-acyloxy propiophenones NH-C OR centres have disappeared owing to the elimination of .mers of the intermediate at some stage of the synthesis,

to obtain the corresponding isomer of the D-threo series solved is an erythro-phenyl .aminopropanediol, it is the L-isomer that is employedand epimerized to. a D-threo compound, the D-isomer being discarded.

As is evident to chemists, the utilization of the forms discarded will become possible if their racemization can beaccomplished. However, every attempt made to obtain'the racemization of said intermediates has failed.

If racemization by heating is tried, the substance decom- L poses before it attains the racemization temperature; it other known methods of racemizati'on are applied,'they fail in the instant case. 5

The present invention derives from the following considerations: Phenylaminopropanediols corresponding to the general formula Y-(13HJHCH20H on 1km Y=NO1 or H (I) have two asymmetrical carbon atoms; this is one of the reasons why they resist direct racemization. If one of .the centres of asymmetry is removed it should be possible to obtain a substance (havingonly one centre of symmetry) whichis susceptible of being racemized.

In fact by, transforming the secondary alcoholic group 'keto group, is expected to be susceptible of being racemized. It is known that substances having onecentre ,of symmetry adjacent to a group that mobilizes a hydrogen atom at the asymmetric carbon, are in the majority of cases racemizable.

For the transformation of the secondary alcoholicgroup of phenyl aminopropanediols into a keto group,

the: known method is to oxidize the N,O-diacyl deriva-,

the acyloxy group in B-position, in the form of an acid, due to the union with the hydrogen in u-position, with -the formation of a non-saturated compound having a double bond between the carbon atoms a and (3. This transformation was recognized recently also on racemic derivatives.

It has been investigated by us thoroughly and we have found the conditions enabling us to obtain true racemization in lieu of said elimination.

We have found that by treating wacylamino-fl-h Aroxypropidphenones corresponding to the general forinstead of the a-acylarnino-fi-acyloxy-propiophen0nes, with substances 6f basic character in aqueous 'ororganic oraqueous-organic medium/in solutioii'or in suspension, at temperatures between 0 and 60? C., but preferably at room temperature 15-30" C.), contrary tothe'case with the corresponding a-acylamino-,fi-acyloxypropio phenones, there does not take place an elimination (of the corresponding hydroxy group) andforma'tion of a double bond, but oirthe' contrar'ya racemi'zationi' 'As substances of basic character; there may bejem ployed inorganic substances such as alkali hydroxides, carbonates and bicarbonates, alkali phosphates etc. as

well as organic substances such as primary, secondary' and tertiary cyclic, heterocyclic, and aliphatic, amines (pyridine, diethylamine,- piper'idine, N-ethylpiperidine, triethylamine, etc), alkali alcoholates and enolates, alkali salts of organic acids and various other basic agents even if notexpressly mentioned herein. Strong alkaline agents (piperidine,N-ethylpiperidine, sodium alcoholate, etc.) are employed in small quantity, about 1%, or in larger amount (500 to 100076) but for a short time (515 minutes);.weak alkaline agents (pyridine, sodium bicarbonate, sodium acetate,.etc.) require a longer time (1. to Days), but they-yield purer products.

In particular, it has been found that sodium bicarbonate, better than the other catalysts, meets the requirements for practical employment, such as low cost, use of an aqueous suspension in lieu of a solution in an organic solvent, reasonably short reaction time (12 to 15 hours), high yield (97% of theory, against 88% with piperidine, 84% with N-ethyl piperidine, with pyridine, 80% with sodium alcoholate).

'perature between C. and 50 C., preferably in the bromate, in the presence of a little hydrobromic acid.

The method of obtaining the a-acylamino-fl-hydroxynon-nitrated compounds are dealt with; if the nitro compropiophenones, which are to be subjected to racemizapounds are treated, reduction is carried out with alumition, is known. The method consists in saponifying caunium isopropylate in isopropyl alcohol or with alkali tiously the a-acylamino-fi-acyloxy propiophenones with boro-hydrides. The D,L-N-acyl phenylaminopropane- HCl and in N-monoacylating the hydrochloride of adiols are thus obtained in the threo and erythro forms, amino-B-hydroxy propiophenones. which are separated by fractional crystallization. The

However, we have found a more rapid method of obthreo derivatives are saponified directly to D,L-threotaining the aforesaid D-ot-acylamino-fl-hydroxypropiophephenyl-amino-propanediols by heating them with diluted nones, namely by oxidizing directly and selectively the HCl. The erythro derivatives are first treated with L-threo or the D-erythro N-acyl derivatives of phenyl- S001 in the cold; a'solution is obtained, which is then substituted aminopropane diols without acylating also decomposed with water and heated to 100 C. for 30 the primary alcoholic group as would be necessary with minutes and thus yields the D,L-threo-phenylaminoconventional methods to protect it from the action of propanediolsn Another method of epimerization applicathe oxidizing agent employed. ble here is treatment of the D,L-erythro-N-acyl phenyl- The process can be carried out bytreating the N-acyl aminopropanediols with SOCl in an inert diluent; the aminodiols with halogens in aqueous solution at a temcorresponding cyclic sulfates are formed which are heated to melting temperature to yield the D,L-transoxazolines; these are subjected to mild saponification, whereby the D,L-threo-N-acyl-phenylaminodiols are obtained.

The following reaction scheme illustrates the sequence of reactions to pass from the L-threo and D-erythro phenyl aminopropanediols to the D,L-threo phenyl aminopresence of actinic light. In lieu of the halogen there can be employed advantageously a compound setting free the halogen, in particular an alkali bromate, e.g. sodium The N-acyl derivatives of phenyl-substituted aminopropanediols can be prepared in various known manners. propanediols.

X=halogen L-threo or D-erythro Y CH--CH-CH2OH Y=NO1 or H;

(g l R=OR=alkyl, haloalkyl,

H NH; aryl.

R00 01 or (RC Obs/ RCOOCH: \EC1+RO Cl JJH NH.C OR NaOH (pH 8) C ORNH1.HC1 (X) 11 NaOH (ph between 7 and 8) RC 0 C1 or (R'COhO 0| L-threo or D- erythro Y C|JH-CJH-CH:O O O R OH NBC 0 R III r a no 0 C101 (ROOMO H20 (H01) D-Y GO-?H-CHlOH( -D-Y CO-(I1H-OH1OH ---D-Y 00-?11-011200011' NH-COR NHa-HCI NELCOR XII I V x1 I IV basal I H V (1) efpimgrigiug I 1 nee e D L Y C O-OE-CHiOH-- D,L-threo and erythro Y- CH-CH-OHiOH--- D L-threo Y- CH-CH-CHaOH O l V v I H2O O l NECOR H NEGOR H NH:

XIII Y VIII 1x Some examples of this invention are recorded below, for illustrating although not limiting purpose, with reference to the general formulae for the reaction scheme.

For instance, they can be made by means of N-mono acylation ofphenyl aminopropanediols with the chloride or the anhydride of an acid in Schotten-Baumann conditions; or by means of treatment, at mild temperature with only a slight excess of the anhydride of an acid, of phenyl- 6O aminopropanediol; or by heating with the lower aliphatic ester, preferably the methyl ester, of an acid; or even by v p I means of partial saponification of tri or di-acyl derivaf a saturated solution of hydrochloric acid in glacial tives of phenyl amino propanediol with alkali hydroxides acetic. acid added and afterwards 100 C 'Of acetyl at mild temperature; or by treating the hydrochlorides of 0s chloride, and the Whole is. let to Stand Overnightphenyl amino propane di l ith th hl id f h the mixture is diluted with 500 cc. of ether to crystallize acids and subsequently treating the intermediate phenylthe h -p y ,3-dia t y- -p p amino diacyloxy hydrochlorides with alkali at pH 3, drochloride (II), which is then filtered off. M.P. 153.5-

In that way, the racemic a-acylamino-fl-hydroxy- 154-5 ()n= methanol)- propiophenones are obtained, which can be transformed 7O of -p y y' into the corresponding aminodiols with known methods. P p hydrochloride are dissolved in 21 of By racemizing the D- -acylamino-p-hydroxypropiophewater, and 3.6 g. Of NaI-ICO dissolved in 300 CC. 0f nones, obtained by proceeding in the way set forth Water are dd at room p r The L-threodhereinbefore the racemic compounds are obtained. pheny1- a m n0-3 ypr p which These are reduced with hydrogen and catalysts, if the fcrystallizes, is filtered off, M.P. 121-122" ,C. {from Example 1 v 1 20.0 g. of L-threo-l-phenyl-1-2-arnino-1,3-propanediol (I) are dissolved in 30 cc. of glacial acetic acid; cc.

J a dios-a Water); t);;.=+6.7i1 (c.=4; methanol). 11.0 g. of L-threo-l-phenyl-2-acetamino-3-acetoxypropane-l-ol (III) are dissolved in 69 cc. of chloroform and oxidized with sodium bichromate and sulphuric acid in aqueous solution. D-a-acetamino-fi-acetoxypropiophenone (IV) is obtained, M.P. l06-108 C. (from ethanol); (a) =36.5 -(c.=4 methanol). 25.5 g: of ,D-wacetamino-5-acetoxypropiophenone (IV) and 40 cc. of concentrated HCl diluted with 32 cc. of water are heated on a water bath till complete dissolution. This solution is vacuum distilled and the residue is taken up with methanol; the D-u-amino- 8-hydroxy-propio-phenone (XI) hydrochloride crystallizes. M.P. 179-180 C.; (a) =42.5i0.5 (c.=2; methanol). 7

8 g. of hydrochloride as above described are dissolved in 70 g. of a mixture of water and ground ice, and 6.5 cc. of benzoyl chloride are added. At a temperature between and C., 10.5 g. of sodium acetate dissolved in cc. of water are added, and the whole is stirred for three hours; the D-u-benzoylamino- 8-hydroxy-propiophenone, when crystallizes is then filtered 01f. M.P. 1338 140 (from ethanol); (u) =+32.5:L1.5 (c.=2:methanol).

10- 1g. of D-zit-benzoylamino-,B-hydroxy-propiophenone are dissolved in a pyridine-triethylamine mixture. After three hours the whole is poured into ice and concen trated hydrochloric acid and the D,L-ot-benzoylarnindflhydroxy-propiophenone, M.P. 141-142 C. (ethanol), is filtered 01$. 10 g. of D,L-oobenzoylamino-B-hydroxypropiophenone, after addition of a small amount of Raney nickel in 100 cc. of methanol, are hydrogenated at 10 at. .until the hydrogen absorption is completed. The catalyst is filtered 01f and then the ethanol solution is concentrated in orderto crystallize the residue, which consist of a mixture of D,L-threo-and erythro-l-phenyl-2-benzoylamino 1,3-propanediol, from which, by crystallization from ethanol water, the D,L-threo-1-phenyl-2-benzoylamino-1,3-propanediol, M.P. 165-167 C., is separated; the latter, saponified by boiling with HCl, gives D,L threo 1 phenyl 2-amino-1,3-propane diol, M.P. 82-84" C.

v V 1 Example 2 10 g. of L- -1-p.nitrophenyl-2-amino-1,3-propane- 'diol (I) are suspended in 24 cc. of saturated hydrochloric acid solution in acetic acid (about 11%) and 16 cc. of acetyl chloride are added. After a night the L-(+)-1-p. nitrophenyl-1,3-diacetoxy-2-arnino propane-hydrochloride (II) is filtered off and purified by crystallizing from methanol-ether. M.P. 170172; (a) =+6.5 (0. 4.18; methanol). 13 g. of L-threo-1-p.nit-rophenyl-1,3- diacetoxy-Z-amono propane hydrochloride (II) are dissolved in 100 cc. of water; 120 cc. of acetone and further at 0 25 cc. of Na H N/ 2 are added. After 2 hours at 0 it is neutralized with HCl N/ 1 and acetone is vacuum distilled. By extraction with ethyl acetate subsequently the L-threo-1-p.nitrophenyl-2acetam-ino-1,S-propanediol (X) is obtained M.P. l34-l36 (c) =-7.65 (c.=5.22; ethanol). 5 cc. of bromine are added under sunlight while stirring at C. to 25.0 of L-threo--p.nitrophenyl-2-acetamino-1,3-propanediol (X) dissolved in 200 cc. of Water. Extraction is made with ethyl acetate, and from the ethylacetate solution the D-pnitrO-a-acetaminofl-hydroxy-propiophenone (XII) is obtained by evaporation. M.P. 142-l44 (a) =+32 (c.=13; pyridine) or =+22.5 (c.=2.0; ethanol). This ketol is obtained also by heating on Water bath a mixture of 30 .g. of D- p.nitro-a-acetamido-fi-acetoxy-propiophenone and 40 cc. of concentrated HCl diluted in 32 cc. of water. As soon as dissolution is over, it is cooled in order to crystallize the hydrochloride of D-pnitro-u-amino-;3-hydroxy-propiophenone (XI) M.P. (a) =--55 (c.=4; H 0). 17 g. of this hydrochloride are mixed with 50 cc. of water; 100 g. of ice and 8 cc. of acetic anhydride, and then a solution of 22 g. of crystallized sodium in 30cc. of water is added. The Dp.nitro-a-acetamido-fl-hydroxy-propiophenone (XII) crystallizes. M.P. 142444 5 g. of D- a-acetamido-B-hydroxy-p.nitropropiophenone (XI I) M.P; 142-144"; (a) =+32 (c.=13; pyridine) are dissolved in 40 cc. of anhydrous pyridine and let to standing at room temperature (about 20 C.) for 140 hours. From the beginning it can be noticed, by sample control that rotatory power decreases in a logarithmic way. When the-racemizat-ion is advanced, the D,L-a-acetylamino-fihydroxy-p.nitropropiophenone (XIII) begins to separate in the form of small yellowish crystalswhich, at the end ofrthe operation, "are collected, washed with a little ether and dried in air.

Alternatively the compound Xmay be transformed into X11, and X11 into XIII, in the following ways:

10 g. of L-threo-l-p.nitrophenyl-Z-acetamino-1,3-propane-diol (X) and 2.2 g. of sodium bromate are dissolved in 120 cc. of water in a flask, and 0.6 g. of 48% hydrobromic acid are added.

The solution is left to stand in the sunlight for one day, then the crystallized D-p.nitro-et-acetamino-B-hydroxy-propiophenone (XII), M.P. 140-142, is filtered off. 10 g. of D-p.nitro-ot-acetamino-B-hydroxy-propiophenone (XII) are suspended in 150 cc. of a 5% sodium bicarbonate solution and stirred from time to time. The solution is left to stand overnight, then the D,L-p.nitrophenyl a acetamino-{3-hydroxy-propiophenone (XIII) M.P. 158-459 C., is filtered off; or

2.5 of D-p.nitrophenyl-a-acetamino-fl-hydroxy-propio-- phenone (XII) (M.P. 142-144"); (a) -=+22.5 (c.=2; ethanol) are dissolved in 20 cc. of ethanol and 75 cc. of N-ethylpiperidine. After a few minutes the D,L-pnitrophenyl-a-acetam-ino-fl-hydroxy-propiophenone (XIIII) begins to separate, showing that racemization has been performed, in the form of small yellow crystals. After 3 hours they are collected and washed with little ether. M.P. 160-163; or

2.5 g. D-p.nitrophenyla-acet-amino-fl-hydroxy-propiophenone (XII) (M.P. 142444 a ,,=+22.5 (c.=2; ethanol) are dissolved in 25 cc. of piperidine. A deep red coloration appears. After 5 minutes this solutionv is poured into 100 g. of ice and 100 cc. concentrated bydrochloric acid. Small yellowish crystals of D,L-pnitrophenyl-u-acetamino-B-hydroxy-propiophenone (XIII) separate, which are collected and dried. M.P. l64166; or

2.5 g. of D-pnitrophenyl-a acetamino-B-hydroxy-propiophenone (XII) (M.P. 142-144) (u) ==+22.5 (c.=2; ethanol) are dissolved in 140 cc. of absolute ethanol and subsequently 10 cc. of an ethanol solution of sodium ethylate (obtained by dissolving 0.25 g. of sodium in 100 cc. of ethanol) are added in the cold. At once a deep red coloration appears. After 5 min. it is neutralized with acetic acid, ethanol is vacuum evaporated and purification is performed by crystallization from dioxane. The

D,L-p.nitro-phenyl-a-acetamino-fi-hydroxy-propiophenone (XIII) is obtained. M.P. 162-163".

25.2 g. of D,L-p.nitro-oz-acetamino-B-hydroxy-propio phenone (XIII) are suspended in cc. of methanol (made free from acid) and 2 g. of 91% potassium borohydride dissolved in 10 cc. of boiled Water are added while stirring and keeping a temperature range from 25 to 30 C. After 20 min. 4 cc. of concentrated HCl are added and the erythro 1 p.nitrophenyl 2 acetamino 1,3-propanediol (VIII) is allowed to crystallize. It has a M.P. 184-l85 V piophenone in a manner substantially analogous to that described in Example 1 for D-a-benzamino-B-hydroxypropiophenone from D-u-acetamino acetoxypropiophenone.

g. of D-p.nitrophenyl-a-propioamino-B-hydroxy-propiophenone (XII) (M.P. l35136); '(0c) =-26.5 (c.=4; ethanol) are dissolved at room temperature in 30 cc. of piperidene. After 5 min. the solution is poured into 100 g. of ice and 100 cc. of concentrated hydrochloric acid. The D,L-p.nitrophenyl-u-propioamino fl-hydroxypropiophenone (XII) separates inthe form of a glue which soon crystallizes. It is collected and dried. M.P. 115-116. V v

4 g. of D-p.nitrophenyl-u-chloroacetamino-p-hydroxypropiophenone (XII) (M.P. fill-102); (a) =+6.4 (c.=4; acetone) are dissolved at room temperature in 25 cc. of pyridine. When rotatory power has disappeared the solution is poured into 100 g. of ice and 75 cc. of concentrated hydrochloric acid. Thus the D,L-p.nitrophenyl a chloroacetamino B hydroxy propiophenone (XIII) separates. M.P. 128130 C.

3 g. of D-p.nitrophenyl-a-benzamino-;8-hydroxy-propiophenone (XII) M.P. 149-150"; (a) =+60 (c.=2; acetone) are dissolved at room temperature in 30 cc. of piperidine. After 10 min. the solution is poured into ice and concentrated hydrochloric acid. The D,L-p.nitrophenyl-a-benzamino- 8-hydroxy-propiophenone (XIII) separates in the form of small crystals. M.P. 157-159".

We claim:

1. The process which comprises treating a compound of the formula YOEH-( H-omon H NECOR 1:

wherein Y is a radical of the group consisting of H and N0 and the COR group is an acyl radical taken from the group consisting of benzoyl, acetyl, propionyl, and monochloracetyl, with an agent of the class consisting of bromine and alkali metal bromates in aqueous solution at a temperature between 0" and +50 C., to obtain a compound of the formula NIELOOR H NH.C O R (X) wherein COR is a radical of the group consisting of benzoyl, acetyl, propionyl, and monochloroacetyl, and Y represents a radical of the group consisting of H and N0 with an agent of the class consisting of bromine and alkali metal bromates, in aqueous solution, and subjecting the so obtained correspondingly optically active compound of the formula NIELC OR (XII) to racemization by treating with a basic racemizing mater1al, to obtain the said 'racemic intermediate which is of the formula.

NH. 0 o R (XIII) -6. The process defined in claim 5, in which the basic racemizing material is taken from the group consisting of pyridine, piperidine, triethylamine, N-ethyl-piperidine, sodium alcoholate, sodium bicarbonate, and sodium acetate.

7. The process which comprises oxidizing a compound of the class consisting of the D- and L-isomers of the compounds of the formula OH NHCOR (X) YQCH-(EH-CHIOH NH.C OR (XII) to racemization by treating with a basic racemizing material, to obtain the said racemic intermediate which is of the formula NH.CO R (XIII) 8. The process defined in claim 7 in which the basic racemizing material is taken from the group consisting of pyridine, piperidine, triethylamine, N-ethyl-piperidine, sodium alcoholate, sodium bicarbonate, and sodium acetate.

9. The process which comprises oxidizing a compound of the class consisting of the D- and L-isomers of the compounds represented by the formula on: NH.COR 1 (X) wherein COR is a radical of the group consisting of benzoyl, acetyl, propionyl, and monochloroacetyl, and Y represents a radical of the group consisting of H and N0 with a stoichiometric amount of sodium bromate in aqueous solution, in the presence of actinic light and hydrobromic acid, at a temperature of from 0 to +50 C., and

subjecting the so obtained correspondingly optically active compound of the formula YGco-cH-omoH I NH. O O R (XII) to direct racemization by treating with aqueous sodium bicarbonate at a temperature not above 60 C., to obtain the said racemic intermediate, which is of the formula NH.C OR (XIII) 10. The process comprising oxidizing a compound of the formula OH NELCOR to a compound of the formula NHCOR by treating the former with an agent of the class consisting of bromine and alkali metal bromates, in aqueous solution, Y being a radical of the group consisting of H and N 0 and the COR group being an acyl radical which provides a stable blocking group in the process.

11. The process which comprises oxidizing a l-phenyl-Z hydroxy-3-acy1amine-4 hydroxy propane compound to an a-aqY1amino-fl-hydroxy-propiophenone by treating the former compound with an agent of the class consisting of bromine and alkali metal bromates, in aqueous solution, said former compound having no other substituents in the 2, 3 and 4 positions.

References Cited in the file of this patent UNITED STATES PATENTS McNamee et a1 Jan. 10, 1939 OTHER REFERENCES Richter: Organic Chemistry, vol. I (1944), p. 393.

10 Alberti et al.: Gazz. Chim. ItaL, vol. 82 (1952),pp. 53, S6, 57, 60 and 62.

Albertiet al.: La Chioca e1 Industria, vol. 33 (1951),

pp. 7-8. 5 Gilman: Organic Chemistry, vol. 2 (1938), pp. 872

and 873.

Fieser and Fiser: Organic Chemistry (1950), pp. 272 to 273.

Scoifone et al.: Gazz. Chimica. Italiana, vol. 81, pp. 10 881-890 (1951).

Vigneaud et al.: Iour. Bio. Chem., vol. 98 (1932), pp. 295-308.

Vigneaud et al.: Jour. Bio. Chem, vol. 99 (1932), pp. 143-151.

UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No.- 2,945,883 July 19, 1960 Carlo Giuseppe Alberti et a1.

ror appears in the above numbered pat- It is hereby certified that er ers Patent should read as ent requiring correction and that the said Lett corrected below.

In the heading to the pr of priority, for "May 20 195 inted specification, line 10, date 3" read May 30, 1953 Signed and sealed this 25th day of April 19610 (SEAL) Attest:

ERNEST W, SWIDER I Attesting Officer DAVID L. LADD Commissioner, of Patents 

1. THE PROCESS WHICH COMPRISES TREATING A COMPOUND OF THE FORMULA 